Prospective Study of DNA Repair Gene Variants in Breast Cancer We propose to prospectively evaluate inherited polymorphisms in DNA repair and related genes with breast cancer risk in a large nested case-control study within the Nurses'Health Study (NHS) with 2096 pathologically confirmed incident breast cancer cases and 2979 matched controls. Specifically, we will comprehensively and systematically evaluate genetic variation in five DNA repair pathways, including base excision repair, nucleotide excision repair, double strand break repair (DNA damage response, homologous recombination and non-homologous end-joining), direct reversal repair, and mismatch repair, along with candidate DNA polymerases and Fanconi Anemia complementation groups. We will survey common genetic variation at each locus using two complementary approaches;1) to evaluate nonsynonymous polymorphisms and 2) to choose tag-SNPs using high-density genotyping data to test for the association of common variants in regions of unknown functional relevance with breast cancer risk. We will evaluate a priori hypothesized interactions between the variants and folate status and antioxidant status (primarily a- and p- carotenes), as measured in pre-diagnostically collected plasma samples, on breast cancer risk. We will have substantial power to detect the main effects of most of the genotypes of interest and interactions between the genotypes and the biomarkers. Our study will add substantially to the body of evidence by evaluating in considerably more detail the roles of common variants in DNA repair genes in breast cancer etiology. Gene- environment interaction analysis involving genetic polymorphisms in DNA repair pathways may provide new insights into the genotoxic effects of exposures on breast cancer risk. Several unique features of the existing NHS cohort include cohort characteristics, quality of design, large sample size, rigor in prospective exposure assessment, high response and follow-up rates, and archived bio-specimens. This innovative work is essential to advance this field, and it has substantial potential for application to other areas of cancer susceptibility.